ABSTRACT The amyloid-? protein (A?) is the most studied amyloid peptide because of its strong association with the neurodegeneration that occurs in Alzheimer?s disease (AD). Abnormally folded A? accumulates in the extracellular space to form insoluble amyloid plaques. However, the lack of correlation between the amount and location of the insoluble amyloid plaques and neurodegeneration has led to the hypothesis that small, soluble, oligomeric assemblies consisting of a mixture of A? peptides, termed soluble A?, are responsible for the death of neurons. We hypothesize that sporadic AD (aka late-onset AD), which accounts for the majority of AD cases, results from the rise in soluble A? levels in the brain. A second hypothesis is that the rise in soluble A? levels results in part from an age-dependent decline of the proteolytic degradation of soluble A?. If these hypotheses are true, then enhancing the proteolytic degradation of soluble A? would be an attractive strategy in the prevention and treatment of sporadic AD. The development of this strategy requires knowledge of the determinants of the proteolytic degradation of soluble A?. Based on extensive preliminary data, we will test two hypotheses. In Specific Aim 1, we will test the hypothesis that the composition of A? species in soluble A? is an important determinant of the proteolytic degradation of soluble A?. This specific aim has three sub-aims: (Aim 1.1) To test the hypothesis that the presence of pyroglutamate-3 A? in soluble A? diminishes the proteolytic degradation of soluble A?; (Aim 1.2) To determine the biophysical basis for the diminished proteolytic degradation of soluble A? containing pyroglutamate-3 A?; and (Aim 1.3) To test the hypothesis that the proteolytic degradation of soluble A? containing pyroglutamate-3 A? to can be enhanced by small molecules including polyphenols and adenosine triphosphate. In Specific Aim 2, we will test the hypothesis that the composition of neuronal membranes is an important determinant of the proteolytic degradation of soluble A?. This specific aim has three sub-aims: (Aim 2.1) To test the hypothesis that the presence of GM1 ganglioside in membranes diminishes the proteolytic degradation of soluble A?; (Aim 2.2) To determine the susceptibility of ?- sheet assemblies formed in the presence of membranes containing GM1 ganglioside to proteolytic degradation; and (Aim 2.3) To test the hypothesis that the proteolytic degradation of soluble A? and ?-sheet assemblies formed in the presence of membranes containing GM1 ganglioside can be enhanced by small molecules including polyphenols and adenosine triphosphate. The execution of the aims of this proposal will facilitate the development of preventive and therapeutic strategies that work by preventing the age-dependent decline of the proteolytic degradation of soluble A? associated with sporadic AD.